Our work in this period has particularly focused on understanding mechanisms implicated in the development of Th17 immune responses at the gingival barrier. The development of Th17 responses at other barriers, such as the skin and gastrointestinal (GI) tract, has been linked to tissue-specific factors, particularly colonization by niche-specific commensals. However, little is known regarding the development of tissue immunity at the oral barrier. Consequently, it is not known how Th17 cells are induced in the oral environment and whether they participate in oral inflammatory disease pathogenesis. Previous work in our laboratory has highlighted unique requirements for homeostatic development of Th17 cells at the oral mucosa. However, the mechanisms implicated in the amplification and dysregulation of Th17 cells in chronic periodontitis are poorly understood. We aimed to characterize the phenotypic and functional characteristics of human periodontitis-associated Th17 cells and to investigate Th17 cell induction and functionality in periodontitis through complementary studies in experimental models and human systems. In lesions of human periodontitis, we documented expansion of memory tissue-resident Th17 cells that secrete cytokines linked to pathogenicity. Mirroring human findings, murine lesions of experimental periodontitis display preferential expansion of Th17 cells (compared to other IL17+ cells) through local proliferation. Whereas health-associated Th17 cells accumulated in a commensal-independent and IL6-dependent manner, in experimental periodontitis the expansion of Th17 cells was triggered by the microbiome. Indeed, in the presence of broad spectrum antibiotics, Th17 cells did not accumulate during experimental periodontitis and disease was arrested, suggesting that microbe-triggered Th17 cells were responsible for disease pathology. In contrast to homeostatic conditions, in periodontitis the expansion of Th17 cells was dependent on both IL6 and IL23. Importantly, we documented that Th17 cells were required for periodontal inflammatory tissue destruction. Selective inhibition of Th17 cell differentiation, using genetic or pharmacological approaches, inhibited periodontal disease. We further showed that Th17-mediated bone loss is dependent on IL17A and the accumulation of neutrophils, as inhibition of IL17 or neutrophil accumulation through antibody treatments conferred protection from bone loss (Figure 1). Thus, our findings demonstrate a divergent regulation of oral Th17 cells in health and disease, support a pathogenic role for Th17 in periodontal bone loss and suggest that Th17/IL17 could be a therapeutic target in the treatment of periodontitis.